Prefrontal Disinhibition in Social Fear: A Vital Action of Somatostatin Interneurons

Abstract

Social fear and avoidance of social partners and social situations represent the core behavioral symptom of Social Anxiety Disorder (SAD), a prevalent psychiatric disorder worldwide. The pathological mechanism of SAD remains elusive and there are no specific and satisfactory therapeutic options currently available. With the development of appropriate animal models, growing studies start to unravel neuronal circuit mechanisms underlying social fear, and underscore a fundamental role of the prefrontal cortex (PFC). Prefrontal cortical functions are implemented by a finely wired microcircuit composed of excitatory principal neurons (PNs) and diverse subtypes of inhibitory interneurons (INs). Disinhibition, defined as a break in inhibition via interactions between IN subtypes that enhances the output of excitatory PNs, has recently been discovered to serve as an efficient strategy in cortical information processing. Here, we review the rodent animal models of social fear, the prefrontal IN diversity, and their circuits with a particular emphasis on a novel disinhibitory microcircuit mediated by somatostatin-expressing INs in gating social fear behavior. The INs subtype distinct and microcircuit-based mechanism advances our understanding of the etiology of social fear and sheds light on developing future treatment of neuropsychiatric disorders associated with social fear.

Keywords: disinhibition; interneuron; prefrontal cortex; social anxiety disorder; social fear.

Figure 1

Specific animal models of social fear. (A) Schematic diagram of the social fear conditioning (SFC) paradigm. The experimental mouse was first allowed to acclimate to the conditioning chamber (Acclimation) and then a stimulus mouse was introduced to one of the stimulus cages placed on opposing corners of the conditioning chamber. During the conditioning session, the experimental mouse was allowed to freely interact with the stimulus mouse, while a foot shock was delivered each time when it approached and investigated the stimulus mouse (Conditioning). After conditioning, the procedure was extended to a longer duration to reinforce behavioral adaption (Post-conditioning). Adapted from Xu et al. (2019). (B) Schematic diagram of sub-chronic social defeat paradigm. For three consecutive days, an unfamiliar aggressive male CD1 intruder mouse (white color) was introduced to the home cage of singly-housed adult C57BL/6J male mice (black color). The intruder was confined within a Plexiglas stimulus cage (10 cm in diameter) for the first 5 min (interaction) and then was allowed to attack the experimental mouse for 10 min (defeat) and withdraw immediately after social confrontations (post-defeat). After 1 week recovery, the expression of social fear to an unfamiliar CD1 mouse was detected in an open field. Social avoidance was assessed by relative time spent in the interaction zone to corner zones.

Figure 2

Recruitment of neocortical disinhibitory microcircuits in fear-related behaviors. Disinhibitory connectivity in the medial prefrontal cortex (mPFC) during social fear expression. Left: the behavioral paradigm of the social fear expression. Right: social stimuli recruit SST⁺ inhibitory interneurons (INs) which strongly inhibit PV⁺ INs and trigger disinhibition of the projecting principal neurons (PNs) in the mPFC.